Combinatorial Chemistry, also known as High Throughput Experimentation, is an emerging area that has impacted various fields. Although still evolving, the procedure is fully established in the pharmaceutical industry. There is increasing interest in applying such techniques in materials science since the combinatorial synthesis method can be a very powerful tool in increasing the rate of experimentation, and therefore, improving the possibility for making discoveries.
The discovery of new materials with novel chemical and physical properties often leads to the development of new and useful technologies. Over forty years ago, for example, the preparation of single crystal semiconductors transformed the electronics industry. Currently, there is a tremendous amount of activity being carried out in the areas of superconductivity, magnetic materials, phosphors, nonlinear optics and high strength materials. Unfortunately, even though the chemistry of extended solids has been extensively explored, few general principles have emerged that allow one to predict with certainty composition, structure and reaction pathways for the synthesis of such solid state compounds. Importantly, it is difficult to predict a priori the physical and chemical properties a particular composition and structure will possess.
Clearly, the preparation of new materials with novel or desired chemical and physical properties is at best happenstance with our current level of understanding. Consequently, the discovery of new materials is limited by the ability to synthesize and analyze new compounds or compositions. As such, there exists a need in the art for a more efficient, economical and systematic approach for the synthesis of novel materials and for the screening of such materials for useful properties.
One of the processes whereby nature produces molecules having novel functions involves the generation of large collections (libraries) of molecules and the systematic screening of those libraries for molecules having a desired property. An example of such a process is the humoral immune system which in a matter of weeks sorts through some 1012 antibody molecules to find one which specifically binds a foreign pathogen (Nisonoff, et al., The Antibody Molecule (Academic Press, New York, 1975)). This notion of generating and screening large libraries of molecules has recently been applied to the drug discovery process. The discovery of new drugs can be likened to the process of finding a key which fits a lock of unknown structure. One solution to the problem is to simply produce and test a large number of different keys in the hope that one will fit the lock.
Using this logic, methods have been developed for the synthesis and screening of large libraries up to 1014 molecules) of peptides, oligonucleotides and other small molecules. Geysen, et al., for example, have developed a method wherein peptide syntheses are carried out in parallel on several rods or pins (see, J. Immun. Meth. 102:259-274 (1987), incorporated herein by reference). Generally, the Geysen, et al. method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. In addition to the Geysen, et al. method, techniques have recently been introduced for synthesizing large arrays of different peptides and other polymers on solid surfaces. Pirrung, et al. have developed a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques (see, U.S. Pat. No. 5,143,854 and PCT Publication No. WO 90/15070, incorporated herein by reference. In addition, Fodor, et al. have developed, among other things, a method of gathering fluorescence intensity data, various photosensitive protecting groups, masking techniques, and automated techniques for performing light-directed, spatially-addressable synthesis techniques (see, Fodor, et al., PCT Publication No. WO 92/10092, the teachings of which are incorporated herein by reference).
Using these various methods, arrays containing thousands or millions of different elements can be formed (see, U.S. Pat. No. 5,424,186, the teachings of which are incorporated herein by reference). As a result of their relationship to semiconductor fabrication techniques, these methods have come to be referred to as “Very Large Scale Immobilized Polymer Synthesis,” or “VLSIPS™ technology. Such techniques have met with substantial success in, for example, screening various ligands such as peptides and oligonucleotides to determine their relative binding affinity to a receptor such as an antibody.
U.S. Pat. No. 5,985,356, issued Nov. 16, 1999, the entire content of which is herein incorporated by reference, discloses the combinatorial synthesis for making and testing an array of novel materials. This patent provides methods and apparatus for the preparation and use of a substrate having an array of diverse materials in predefined regions thereon. A substrate having an array of diverse materials thereon is prepared by delivering components of materials to predefined regions on the substrate, and simultaneously reacting the components to form at least two materials. Materials which can be prepared using the methods and apparatus of the present invention include, for example, covalent network solids, ionic solids and molecular solids. More particularly, materials which can be prepared include inorganic materials, intermetallic materials, metal alloys, ceramic materials, organic materials, organometallic materials, non-biological organic polymers, composite materials (e.g., inorganic composites, organic composites, or combinations thereof), etc. Once prepared, these reaction products can be screened in parallel or sequentially for useful properties including, for example, electrical, thermal, mechanical, morphological, optical, magnetic, chemical and other properties. As such, the patented invention provides methods and apparatus for the parallel synthesis and analysis of novel materials having new and useful properties.
In one embodiment of U.S. Pat. No. 5,985,356, a first component of a first material is delivered to a first region on a substrate, and a first component of a second material is delivered to a second region on the same substrate. Thereafter, a second component of the first material is delivered to the first region on the substrate, and a second component of the second material is delivered to the second region on the substrate. The process is optionally repeated, with additional components, to form a vast array of components at predefined, i.e., known, locations on the substrate. Thereafter, the components are simultaneously reacted to form at least two materials. The components can be sequentially or simultaneously delivered to predefined regions on the substrate in any stoichiometry, including a gradient of stoichiometries, using any of a number of different delivery techniques.
In another embodiment, a method is provided for forming at least two different arrays of materials by delivering substantially the same reaction components at substantially identical concentrations to reaction regions on both first and second substrates and, thereafter, subjecting the components on the first substrate to a first set of reaction conditions and the components on the second substrate to a second set of reaction conditions. Using this method, the effects of the various reaction parameters can be studied on many materials simultaneously and, in turn, such reaction parameters can be optimized. Reaction parameters which can be varied include, for example, reactant amounts, reactant solvents, reaction temperatures, reaction times, the pressures at which the reactions are carried out, the atmospheres in which the reactions are conducted, the rates at which the reactions are quenched, the order in which the reactants are deposited, etc.
In the delivery systems of the patented invention, a small, precisely metered amount of each reactant component is delivered into each reaction region. This may be accomplished using a variety of delivery techniques, either alone or in combination with a variety of masking techniques. For example, thin-film deposition in combination with physical masking or photolithographic techniques can be used to deliver various reactants to selected regions on the substrate. Reactants can be delivered as amorphous films, epitaxial films, or lattice and superlattice structures. Moreover, using such techniques, reactants can be delivered to each site in a uniform distribution, or in a gradient of stoichiometries. Alternatively, the various reactant components can be deposited into the reaction regions of interest from a dispenser in the form of droplets or powder. Suitable dispensers include, for example, micropipettes, mechanisms adapted from ink-jet printing technology, or electrophoretic pumps.
Once the components of interest have been delivered to predefined regions on the substrate, they are reacted using a number of different synthetic routes to form an array of materials. The components can be reacted using, for example, solution based synthesis techniques, photochemical techniques, polymerization techniques, template directed synthesis techniques, epitaxial growth techniques, by the sol-gel process, by thermal, infrared or microwave heating, by calcination, sintering or annealing, by hydrothermal methods, by flux methods, by crystallization through vaporization of solvent, etc. Thereafter, the array can be screened for materials having useful properties.
Similar to the formation of a large array of compositions as described in U.S. Pat. No. 5,985,356, is a technique for forming an array of different compositions, including metal alloys wherein the individual components that form the composition are applied by thin film deposition as continuous concentration gradients across a sheet. J. J. Hanak, “The ‘Multiple-Sample Concept’ in Materials Research: Synthesis, Compositional Analysis and Testing of Entire Multicomponent Systems”, Journal of Materials Science 5 (1970) 964-971 discusses the development of multicomponent synthesis including the use of a technique of co-evaporating or co-sputtering two or more elements from different, physically separated sources onto a suitable substrate. In one experiment, almost the entire composition continuum of a given binary or ternary system was deposited on one substrate. Specimens made by the foregoing techniques have to be analyzed for chemical content point by point by existing chemical or physical methods. Thus the advantage gained by the synthesis technique was all but lost in the analytical methods. The article discloses that a unique computerized analytical method was developed based on the measurement of a simple extensive property common to all deposited films, namely, the thickness. In order to obtain analysis for the entire composition range the only required measurements are the two thickness measurements for a given binary system or three such measurements for a ternary system. The development of the computerized analysis is stated to have meant the removal of the main obstacle to the realization of the multiple sample concept. Goldfarb, et al., “Novel Sample Preparation Technique for the Study of Multiple Component Phase Diagrams”, Materials Letters 21 (1994) 149-154, provides a technique for alloy sample preparation based on thin film deposition, for a study of binary and ternary compositions. Thin elemental wedge-shaped layers of the components were gradually sputtered in an alternating manner to form a multi-layered structure. The samples obtained had compositions which depended upon the location of the substrate. Such samples, containing differently composed Au—Ag—Cu alloys were heat treated to promote formation of stable phases. The alloys formed were studied by x-ray diffraction and various microscopic techniques. The article demonstrates the advantages of the disclosed method over conventional bulk-based methods. A similar approach was taken to evaluate alternative thin-film dielectrics as described in Letters to Nature, “Discovery of a Useful Thin-film Dielectric Using a Composition-Spread Approach”, R. B. van Dover, et al., Nature (vol. 392) 12 Mar. 1998. In this article, a wide range of compositions were efficiently evaluated by using a technique of depositing a single film with a ternary composition spread on a sheet and evaluating the critical properties as a function of position on the sheet which is directly related to material composition using an automated tool, the continuous composition spread technique.
Different from new materials in which new chemical compounds are formed from reaction mixtures of distinct reaction elements or compounds, or alloys, which are solid solutions of two or more components, are composite materials, which typically comprise one, or more components arranged as unreacted mixtures or layers. Composite materials are widely used for industrial and consumer use and are formed based upon the idea that a mixture of components can yield a better property configuration than a single base component. Among the numerous objects which can be formed as composites, non-limiting samples include heterogeneous catalysts, adsorbents for gas or liquid separations and pigments. Heterogeneous catalysts, for example, are widely used for industrial processing and/or in consumer goods, such as, for example, as oxidation catalysts contained in catalytic converters of automobiles. As opposed to new compounds from deposited reactive layers, the chemical compositions which form the distinct deposited compounds of heterogeneous catalysts remain mostly distinct from the other compounds. The activity of particular catalysts, the selectivity to achieve the desired product, thermal, hydro and hydrothermal stabilities of the heterogenous catalysts often depend upon the distinct layered configuration of the deposited metal, metal oxide or other compounds as well as the distinct composition of each layer and/or thickness of each layer which are deposited to form the heterogeneous catalytic material. Moreover, often the heterogenous catalyst is supported on a metallic or ceramic support which although may be neutral with respect to the chemical reactants contacting the catalyst, may have a physical or chemical effect on the catalytic components in immediate contact or approximate to the support. Thus, for catalytic converters, cordierite honeycombs are typically coated with one or more washcoats of catalytic layers. It is not uncommon for the cordierite substrate to alter the catalytic properties of the layer or layers in contact or proximate contact with the substrate such that differences between contemplated and actual results achieved with the catalyst may disadvantageously exist.
The present invention is not intended to be limited to heterogeneous catalysts. Many base components are mixed with additives to adjust a variety of physical, chemical and/or electrical properties. Among non-limiting examples, are porous, crystalline adsorbents, which are combined with other major or minor phases to modify adsorption properties, improve throughputs, provide for improved selectivity of adsorbed components, etc. Pigment bases are provided with additives to improve color, luster, strength, flowability, etc. Plastic composites are formed to provide tailored physical properties, to provide thermal, UV, moisture stabilities, improved over the base resin.
Regardless of the use of the composite, there is usually a need to test different compositions, configurations of compositional layers and/or relative concentrations of the components with respect to each other. Accordingly, an enormous problem exists with respect to testing the numerous possible combinations of materials used to form a composite. The variables for making a composite are still huge even if the composition of the composite is known and selected inasmuch as the arrangement (configuration) of layers, if used, and/or concentration of the individual components with respect to the other components still need to be tested for the desired properties which are sought.